Antisense oligonucleotide technology offers a unique form of drug therapy; however, one of the problems facing this technology is the difficulty that these types of molecules have in penetrating biological membranes to get to their site of action. The long term objectives of this research program are to develop glycosteroid-oligonucleotide conjugation technology for the effective delivery of antisense therapies across biological membranes thus making antisense technology a more effective and real form of drug therapy. The specific aim of this work will be to conjugate bis-glycosylated steroid membrane permeation enhancers to antisense oligonucleotide sequences known to inhibit HIV replication with the possibility of developing an effective anti-HIV drug therapy. This conjugation will be accomplished by attaching to the 5'- or 3' terminus of either the antisense splice acceptor or primer binding site sequences, which are known to be important in HIV replication, a glycosylated steroid via a linker to the steroid C-17 side chain. The ability of these new conjugates to bind to the target sense sequences also will be studied. The development of a technology that would reliably deliver antisense oligonucleotides both across cellular and mucosal membranes could provide effective new drugs.